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Understanding the functional role of Myeloid Derived Suppressor cells in tuberculosis

了解骨髓源性抑制细胞在结核病中的功能作用

基本信息

批准号：
10440359
负责人：
Deepak Kaushal
金额：
$ 86.92万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-06 至 2022-09-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440359
关键词：
Advanced Development Animal Model Automobile Driving B-Lymphocytes BCG Live Bronchus-Associated Lymphoid Tissue Cessation of life Characteristics Chronic Clinical Data Disease Drug resistant Mycobacteria Tuberculosis Genes Granuloma Human Hypoxia Inducible Factor Immunity Immunologics Infection Control Interleukin-17 Knowledge Lung Macaca Mediating Modeling Molecular Mus Mycobacterium bovis Mycobacterium tuberculosis Myeloid Cells Myeloid-derived suppressor cells Pathway interactions Population Predisposition Production Proteins Publishing Pulmonary Tuberculosis Relapse Role S100A8 gene Signal Pathway Signal Transduction T cell response T-Lymphocyte Therapeutic Translations Tretinoin Tuberculosis Vaccines cell type cytokine extensive drug resistance improved in vivo inhibitor mouse model neutrophil nonhuman primate novel therapeutics prevent transcription factor translational study tuberculosis treatment

项目摘要

PROJECT SUMMARY. Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), is estimated to infect one-fourth of the world's population, resulting in approximately 1.6 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb infection. The tubercle granuloma is long been considered a hallmark of TB. Our published data suggest that the presence of inducible bronchus-associated lymphoid tissue (iBALT)-containing granulomas is indicative of protective granulomas that mediate Mtb control during TB latency. In contrast, infiltrating myeloid derived suppressor cells (MDSCs) as well as neutrophils producing proinflammatory molecules are characteristic of non-protective granulomas during pulmonary TB. MDSCs are induced during pulmonary TB in humans, nonhuman primates (NHPs) and mice and suppress protective T cell responses. Our new data show a protective role for the proinflammatory cytokine, Interleukin (IL)-17 in dampening lung MDSC accumulation and limiting T cell suppression in the lung during TB. Additionally, we show that the MDSC-derived proinflammatory proteins, S100A8/A9 heterodimers are induced upon Mtb infection in humans, NHPs and mice. Furthermore, S100A8/A9-expressing myeloid cells accumulate within the tubercle granuloma and amplify lung MDSC accumulation to mediate Mtb susceptibility. In the current proposal, using mouse and NHP models of TB, we will elucidate the mechanism(s) which regulate and promote MDSC accumulation during TB, and characterize whether MDSCs and their pathways can be targeted as host-directed therapeutics (HDTs) for TB. In Specific Aim 1, using gene deficient and conditional gene deficient mouse models we will determine the IL-17-dependent pathways that limit MDSC accumulation during TB. In Specific Aim 2, we will evaluate the role of S100A8/A9 proteins in driving MDSC accumulation and susceptibility to TB, and also determine whether blocking S100A8/A9 signaling will limit TB relapse. Finally, in Specific Aim 3 we will evaluate if MDSC depletion can prevent TB progression in nonhuman primates (NHPs). At the completion of the aims proposed here, we will have considerably expanded our understanding of the Mtb-specific signaling pathways and factors that positively (S100A8/A9 pathways) and negatively (IL-17 dependent pathways) regulate MDSC accumulation during TB. Additionally, our translational studies in NHPs will enable the use of HDTs to limit MDSCs during TB.

项目总结。结核分枝杆菌（Mtb），该疾病的病原体